Method of producing crystals of nordihydroguaiaretic acid



Patented ay 27, 194? so res 2,421,109 METHOD or rnonncmc CRYSTALS or" NORDIHYDROGU ETIC ACID Joseph Adams, Chicago, Ill., assignor, by mesne assignments, to. Regents of the University of Minnesota, Minneapolis, Minn, a corporation of Minnesota No Drawing 7 Claims.

Application June 22, 1944, eriai No. 541,860

My invention has for its object the provision of an industrially practicable method of producing merchantable crystals of the anti-oxidant nordihydroguaiaretic acid.

An object and accomplishment of my invention is the production of original crystals of nordihydroguaiaretic acid that are pure and free from odoriferous contaminants, and thus admirably two selective solvents.

of the two selective solvents one is watermiscible; nordihydroguaiaretic acid is readily soluble in it but cannot be crystallized from it. The other solvent is water immiscible but miscible with the first solvent; nordihydroguaiaretic acid is only slightly soluble in it but can be crystallized out of it.

These and other objects, features and advantages of my invention presently will appear.

The material wherewith my method begins consists of some or all of the woody portions, leaves, stems, flowers, and buds of the so-called creosote bush (botanically named Larrea dwaricata) or, and preferably, an acidulatedalkali or alcoholic extraction thereof.

In the practice of my method a suitable quantity of the starting material is. digested with a water-miscible solvent (e. g., anhydrous methyl alcohol) that has been ascertained to be a very good solvent for nordihydroguaiaretic acid. When the soluble constituents of the starting material are in solution I dilute the water-miscible solvent with a very much larger (e. g., twenty-five times as large) quantity of a second or water-immiscible solvent (e. g., ethylene dichloride) that has been ascertained tobe one in which nordihydroguaiaretic acid is only slightly soluble, but which is miscible with the first or water-miscible solvent. The insoluble substances in the mixed solvents are now removed, preferably by filtering. to prevent any emulsificationof the solvents in the next step of the method. All of the foregoing preferably is accomplished under anhydrous conditions.

The mixed solvents are then subjected to vigorous agitation while there is being added thereto an amount of water substantially larger (e. g., four times as large) as the amount of the first or water-miscible solvent. By and as the result of this operation, which desirably is effected without permitting the temperature of the mixed liquids to fall substantially below 115 F., the first or water-miscible solvent is washed from the second or water-immiscible solvent, and such waterimmiscible solvent takes unto itself from said water-miscible solvent certain very finely dispersed particles including nordihydroguaiaretic acid--this transfer of solutes occurring because they are not soluble in the aqueous dilution of the water-miscible solvent. The agitation should be continued long enough to insure complete divorcement of the water-miscible solvent from the water-immiscible solvent. 7

After the period of agitation, the two resultant immiscible liquids are permitted to settleand are then separated. The one of such liquids which includes the second or water-immiscible solvent is then filtered to remove all foreign matter not in, solution.

Such liquid is then substantially concentrated, preferably by being heated in vacuo, in sumcient degree (e. g., nearly so that when it is subsequently subjected to controlled cooling and aided by agitation of theliquid, precipitates, first, a resinous red phenolic by-product and, second, a delayed crystal formation of nordihydroguaiaretic acid.

When such liquid has reached under controlled cooling a temperature 01' between 70 F. and 80 F., a resinous red phenolic by-product is precipitated and removed by filtration.

When by continuance of such controlled cool ing the liquid has attained a temperature of approximately F., it preferably is subjected to agitation which aiyls the development and precipitation of a, delayed crystal formation of nordihydroguaiaretic acid. These first crystals of nordihydroguaiaretic acid are removed from the liquid by filtration.

Next th liquid is again substantially concentrated (e. g., by 50%) preferably by being heated in vacuo, and is again subjected to controlled cooling to between F. and F., when an.- other precipitation of-the resinous redvphenolic by-product is removed by filtration. controlled cooling of the liquid to approximately 60 F., plus agitation, again causes the formation of a substantial quantity of crystals. These are removed irom the liquid by filtration and dried.

Further The liquid is next for a third time substantially concentrated (e. g., by 50%), preferably by being heated in vacuo, and is again subjected to controlled cooling down to between 70 F. and 80 F.', when another precipitation of the resinous red phenolic by-product is removed by filtration. Further=controlled cooling of the liquid to approximately 60 F.. plus agitation, enables me to.

realize a third substantial harvestof merchant- -able crystals of nordihydroguaiaretic acid.

In my method each harvest of crystalline antioxidantis preceded by precipitation and removal of the red phenolic by-product. This is of great importance; otherwise. the resultant occlusion of the red phenolic lay-product by the crystals would deprive the crystals of their essential purity.

While I prefer to employ methyl alcohol as my water-miscible solvent, I may use in lieu thereof various other water-miscible monohydroxy or polyhydroxy alcohols, such, for examples, as ethyl alcohol, isopropyl alcohol, propylene glycol and ethylene glycol; and while I prefer to employ ethylene dichloride as my watch-immiscible solvent, I may use in lieu thereof various chlorinated hydro-carbons such as chloroform, methylpracticing the invenrived from 100 lbs. of the young branches and leaves of the so-called creosote bush is digested with 3 gallons of hot 100% methyl alcohol. The resultant alcoholic sludge is then diluted with 75 gallons of ethylene dichloride. It is then heated to 130 F. and filtered to remove all insoluble fractions. The miscible liquids are then violently agitated while 12 gallons of water is added thereto to wash the methyl alcohol from the ethylene dichloride and to transfer from the methyl alcohol to the ethylene dichloride certain finely dispersed particles, including nordihydro uaiaretic acid, which have greatly reduced solubility' in a 20% solution of methyl alcohol in water. During the addition oi the water, the tem erature of the liquids is not permitted to fall below 115 F. The agitation is continued for 20 minutes, the two immiscible liquids resulting from the addition of water and the agitation .(i. e., (a) the aqueous alcohol solution, and (b) the ethylene dichloride and the solutes transferred to it) are permitted to settle for minutes and are then separated. The ethylene dimoved by filtration. The temperature of the ethylene dichloride is then lowered to 60 F., and a crystal formation 01' nordihydroguaiaretic acid is again developed by agitation. The crystals thus developed are removed by filtration. They are of commercial quality. The gallons of ethylene dichloride is next concentrated to 10 gallons, is again cooled down to 70 F., and then filtered to yield an additional quantity of the resinous red phenolic by-product. Its temperature is then againlowered to 60 a crystal formation of the anti-oxidant is again developed by agitation, and the resultant crystals, which also are of commercial quality, are removed by filtration. Further concentration of the ethylene dichloride followed by subsequent controlled temperature reductions and filtrations, will yield a relatively low crop of crystals of the anti-oxidant plus a relatively. large percentage of a gummy resinous product of a phenolic nature having much greater solubility in ethylene dichloride than any other previously precipitated resinous fraction. This gummy resinous residue may be collected until a. sufilcient accumulation warrants further dilution with ethylene dichloride followed by concentrations, controlled temperature reductions and filtrations, to reclaim in the form of merchantable crystals any nordihydroguaiaretic acid that may be present. 1

Reference is made to copending application of Ole Gisvold, Serial N0. 490,149, filed June 9, 1943. An acldulated alkali extraction of the creosote bush, prepared in accordance with the teachings of said Gisvold application, is a material suitable for treatment in accordance with my present invention.

Having thus described m invention, what I claim as new and desire to secure by Letters Patent of the United States is: l

1. The process of producing nordihydroguaiae retlc acid which comprises extracting an acidulated alkali extract of plant material of the species Larrea divaricata containing nordihydroguaiaretic acid, with a first solvent selected from the group consisting of water miscible mono and polyhydric low aliphatic alcohols to produce a solution of nordihydroguaiaretic acid, adding to chloride fraction is then filtered. It is then concentrated, by being heated in vacuo, from 75 galions to 40 gallons. Controlled cooling of the concentrated solvent follows. when its temperature reaches 70 F., it is filtered to remove a resinous phenolic fraction. Further cooling of the concentrated solvent to F., plus constant agitation, results in a delayed crystal formation of nordihydroguaiaretic acid. The crystals from this first stage of crystallization are removed by filtration. They are of merchantahle quality. The ethylene dichloride is next further concentrated from 40. gallons to 20 gallons, and is again cooled down to F. when there is precipitated a red resinous phenolic by-product which is resaid solution a second solvent miscible with said first solvent, said second solvent being selected from the group consisting of monocyclic aromatic hydrocarbons and halogenated low aliphatic hydrocarbons,. washingthe mixture with water to remove the first solvent and crystallizlng nordihydroguaiaretic acid from the second solvent.

2. The process of producing nordihydroguaiaretic acid which comprises extracting an acidulated alkali extract of plant material of the species Larrea divaricata containing nordihydroguaiaretic acid, with a first solvent selected from the group consisting of water miscible mono and polyhydrlc low aliphatic alcohols to produce a solution of nordihydroguaiaretic acid, adding to said solution-a much greater quantity of a second solvent miscible with said first solvent, said second solvent. being selected from the group consisting of monocyclic aromatic hydrocarbons. and halogenated low aliphatic hydrocarbons, introducing 3. The process of producing nordihydroguaiaretic acid which comprises extracting an acidulated alkali extract of plant material of the species Larrea divaricata containing nordihydroguaiaretic acid, with a low aliphatic monohydric alcohol to produce a solution of nordihydroguaiaretic acid, adding to said solution-a halogenated low aliphatic hydrocarbon miscible with said alcohol, washing the mixture with water to remove the alcohol, and crystallizing the nordihydroguaiaretic acid from the halogenated hydrocarbon.

4. The process of producing nordihydroguaiaretic acid which comprises extracting an acidulated alkali extract of plant material of the species Larreu. divaricata containing nordihydroguaiaretic acid, with methyl alcohol to produce a solution of nordihydroguaiaretic acid, adding ethylene dichloride to said solution, washing the mixture with water to remove the methyl alcohol and crystallize nordihydroguaiaretic ,acid from the ethylene dichloride.

5. The process 'of producing nordihydroguaiaguaiaretic acid, with retic acidwhich comprises extracting an acidulated alkali extract of plant material of the species Larrea divaricata containing nordihydroguaiaretic acid, with a first solventselected from the group consisting of water miscible mono and polyhydric low aliphatic alcohols to produce a solution of nordihydroguaiaretic acid, adding to said solution a second solvent miscible with said first solvent, said second solvent being selected from the group consisting of monocyclic aromatic hydrocarbons and halogenated low aliphatic hydrocarbons, washing the mixture with water to remove the first solvent, concentrating the second solvent, permitting it to cool to approximately from 70 F. to 80 F., removing a precipitated resinous red phenolic by-product, cooling the second solvent further to approximately 60 F. to crystallize nordihydroguaiaretic acid and removing the nordihydroguaiaretic acid crystals.

6. The process of producing nordihydroguaia- 2 retic acid which comprises extracting an acidulated alkali extract of plant material of the species Larrea divaricata containing nordihydro methyl alcohol to produce a solution of nordihydroguaiaretic acid, adding ethylene dichloride to said solution, washing the mixture with water to remove the methyl alcohol, concentrating the ethylene dichloride solution, cooling it to approximately F. to F., removing a precipitated resinous red phenolic byproduct, cooling the ethylene dichloride solution to approximately 60 F. to crystallize nordihydroguaiaretic acid and separating the nordihydroguaiaretic acid crystals.

7. The process of producing nordihydroguaiaretic acid which comprises extracting an acidulated alkali extract of plant material of the species Lam-ea divaricata containing nordihydroguaiaretic acid, with methyl alcohol to produce a solution of nordihydroguaiaretic acid, adding to the resultant solution'ethylene dichloride in an amount approximately twenty-five times the amount of the methyl alcohol,adding to the resultant mixture water in an amount approximately four times the amount of alcohol, sepa-' REFERENCES CITED The following references are .of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,113,714 Taub Oct. 13, 1914 1,250,132 Blundell Dec. 18, 1917 2,096,922 Sankowsky Oct. 26, 1937 2,098,254 Mattill Nov. 9, 1937 2,318,748 Buxton'; May 11, 1943 1,758,616 McGavack May 13, 1930 2,209,019 Slagh July 23, 1940 

